TY  - JOUR
AU  - Schmitt, Katrin
AU  - Molfenter, Britta
AU  - Koerich Laureano, Natalia
AU  - Tawk, Bouchra
AU  - Bieg, Matthias
AU  - Pastor Hostench, Xavier
AU  - Weichenhan, Dieter
AU  - Ullrich, Nina D
AU  - Shang, Viny
AU  - Richter, Daniela
AU  - Stögbauer, Fabian
AU  - Schroeder, Lea
AU  - de Bem Prunes, Bianca
AU  - Visioli, Fernanda
AU  - Varvaki Rados, Pantelis
AU  - Jou, Adriana
AU  - Plath, Michaela
AU  - Federspil, Philippe A
AU  - Thierauf, Julia
AU  - Döscher, Johannes
AU  - Weissinger, Stephanie E
AU  - Hoffmann, Thomas K
AU  - Wagner, Steffen
AU  - Wittekindt, Claus
AU  - Ishaque, Naveed
AU  - Eils, Roland
AU  - Klussmann, Jens P
AU  - Holzinger, Dana
AU  - Plass, Christoph
AU  - Abdollahi, Amir
AU  - Freier, Kolja
AU  - Weichert, Wilko
AU  - Zaoui, Karim
AU  - Hess, Jochen
TI  - Somatic mutations and promotor methylation of the ryanodine receptor 2 is a common event in the pathogenesis of head and neck cancer.
JO  - International journal of cancer
VL  - 145
IS  - 12
SN  - 1097-0215
CY  - Bognor Regis
PB  - Wiley-Liss
M1  - DKFZ-2019-01444
SP  - 3299-3310
PY  - 2019
AB  - Genomic sequencing projects unraveled the mutational landscape of head and neck squamous cell carcinoma (HNSCC) and provided a comprehensive catalogue of somatic mutations. However, the limited number of significant cancer-related genes obtained so far only partially explains the biological complexity of HNSCC and hampers the development of novel diagnostic biomarkers and therapeutic targets. We pursued a multi-scale omics approach based on whole-exome sequencing, global DNA methylation and gene expression profiling data derived from tumor samples of the HIPO-HNC cohort (n=87), and confirmed new findings with datasets from The Cancer Genome Atlas (TCGA). Promoter methylation was confirmed by MassARRAY analysis and protein expression was assessed by immunohistochemistry and immunofluorescence staining. We discovered a set of cancer-related genes with frequent somatic mutations and high frequency of promoter methylation. This included the ryanodine receptor 2 (RYR2), which showed variable promoter methylation and expression in both tumor samples and cell lines. Immunohistochemical staining of tissue sections unraveled a gradual loss of RYR2 expression from normal mucosa via dysplastic lesion to invasive cancer, and indicated that reduced RYR2 expression in adjacent tissue and precancerous lesions might serve as risk factor for unfavorable prognosis and upcoming malignant conversion. In summary, our data indicate that impaired RYR2 function by either somatic mutation or epigenetic silencing is a common event in HNSCC pathogenesis. Detection of RYR2 expression and/or promoter methylation might enable risk assessment for malignant conversion of dysplastic lesions. This article is protected by copyright. All rights reserved.
LB  - PUB:(DE-HGF)16
C6  - pmid:31135957
DO  - DOI:10.1002/ijc.32481
UR  - https://inrepo02.dkfz.de/record/143882
ER  -